Macular degeneration is a disease of the eye that results in minor to severe impairment of the subject's sharp central vision, which is necessary for activities such as reading and driving. Age-related macular degeneration (“AMD”) afflicts an estimated 30 to 50 million people worldwide and is the leading cause of severe vision loss in Western societies. Normal vision occurs when light enters the front of the eye and is focused by the lens onto highly sensitive and fragile cells called photoreceptors that line the inside of the back of the eye. Together with other neurons the photoreceptors make up the retina of the eye. The macula is the portion of the retina located near the center of the back of the eye that contains the fovea, which is responsible for sharp central vision. Like all cells, the photoreceptors need a constant supply of oxygen and nutrients; however, due to the sensitive nature of the structure of the retina it is not vascularized. Instead, the retina is fed by the choroid, a highly vascular layer outside the retina. The oxygen and nutrients from these blood vessels are transported to the retina across Bruch's membrane which consists of a layer of pigmented epithelium and layers of connective tissue.
AMD disrupts the photoreceptors of the macula in one of two ways: (1) deposits of extracellular debris between Bruch's membrane and the retinal pigment epithelium known as “dry” macular degeneration and (2) breaks in Bruch's membrane that allow angiogenic blood vessels from the choroid to penetrate the retinal pigment epithelium known as “wet” macular degeneration. Dry AMD progresses slowly and is responsible for about 90% of AMD worldwide. Wet AMD can be sudden, severe and irreversible due to bleeding and scarring of the macular region including the fovea. Although wet AMD accounts for only 10% of AMD worldwide it is responsible for 90% of AMD-associated blindness.
The intraocular neovascularization that occurs in wet AMD is confined to the macula but it may also occur at other places in the uveal tract including the adjacent posterior pole and even more anteriorly at the trabecular meshwork of the iris root. Such neovascularization can occur from a variety of pathologies other than AMD including but not limited to proliferative disorders, infectious disorders, genetic disorders, vascular diseases, exudative diseases, uveitis, retinitis, choroiditis, trauma including surgery and other causes of ischemia or angiogenesis.
Vascular endothelial growth factor receptor (“VEGFR”) pathways are the main pharmaceutical targets of angiogenic suppression. Anti-angiogenesis drugs that target VEGFR pathways and are used in the eye include pegaptanib (Macugen®; Macugen is a registered trademark of Eyetech, Inc.), bevacizumab (Avastin®; Avastin is a registered trademark of Genentech, Inc.) and ranibizumab (Lucentis®; Lucentis is a registered trademark of Genentech, Inc.). However, each of these drugs is administered in the form of an injection due to their relatively large size and poor absorption. Additionally, these drugs are expensive to administer. For example, ranibizumab can cost up to $48,000 for the two-years of recommended treatment. Perhaps more prohibitive than the cost is the side effects of these intraocularly injected drugs including redness or petechial hemorrhage in the white part of the eye, eye pain lasting for several hours, cataracts, vitreous floaters (i.e. specks in your vision), increase pressure within the eye, inflammation of the eye, blurred vision, eye irritation, and most prohibitive, risk of endophthalmitis.
Additional tyrosine kinase receptors (“ancillary receptors”) involved in angiogenesis have also been discovered. The suppression of these ancillary receptors is known to enhance the anti-angiogenic effect of VEGFR pathway suppression. These ancillary receptors include platelet-derived growth factor receptors (“PDGFR”) α and β, fibroblast-derived growth factor receptors (“FDGFR”) 1-4, c-KIT, and TIE 1-3. Suppression of two or more of these ancillary receptors in conjunction with suppression of a VEGFR is common in the art and is known as multi-receptor tyrosine kinase inhibition. Multi-receptor tyrosine kinase inhibition for treatment of angiogenesis is known to decrease the incidence and severity of tachyphylaxis or resistance in response to suppression of a VEGFR alone. Pharmaceuticals used in multi-receptor tyrosine kinase inhibition generally have high degrees of lipophilicity with insufficient penetration to the posterior pole of the eye and those with sufficient penetration have an insufficient duration of activity. Many of the molecules used in multi-receptor tyrosine kinase inhibition have a risk of severe systemic side effects due to their chemotherapeutic side effects with high systemic absorption. Attempts to overcome these insufficiencies and side effect include slow release intra-vitreal implants as described in U.S. Pat. Nos. 8,481,069 and 8,465,778. However, intra-vitreal implants have their own disadvantages including pain, transient blurring of vision for tens of minutes to hours, major risks and expense of an intraocular surgical procedure including need for possible implant removal, greater risk of fulminant endophthalmitis, acute or indolent inflammation with cystoids macular edema, vitritis, cyclitis, retinal detachment, choroidal effusion and toxicity form dissolution of the implant membranes.
Thus, there is a need in the art for an ophthalmological composition and methods that can deliver sufficient amounts of these poorly absorbed and difficult to solubilize drugs intraocularly to the posterior of the eye where wet AMD and several other angiogenic disease processes occur. These compositions should be cheap to produce and these methods should be easy to perform, such as with topological compositions or subconjunctival injections, thus avoiding the expense, inconvenience and morbidity of repeated intra-vitreal injections. Furthermore, these compositions and methods should avoid expensive and invasive surgical procedures, such as the intra-vitreal implant. Additionally, these ophthalmological compositions and methods should be able to achieve topological delivery to the posterior of the eye without high systemic absorption of anti-angiogenic drugs that often lead to system toxicities including severe bleeding, disturbed wound healing, gastro-intestinal perforation, hypertension, fatigue, and on rare occasions, death. Finally, these ophthalmological compositions and methods should have improved efficacy over commercially available treatments for wet AMD and other diseases caused by intraocular neovascularization via reduction or elimination of resistance and tachyphylaxis.